The past several years have seen major progress in the delivery of treatment and care to HIV-infected people in the developing world. However, substantial uncertainty persists regarding optimal treatment strategies, the cost of second- and third-line antiretroviral treatment, and the impact of expanded care. As the HIV epidemic continues to grow, these problems require critical analysis. In 2004, NIAID awarded our research group funding to develop the "Cost-effectiveness of Preventing AlDS Complications (CEPAC) International" Model, a computer simulation of the natural history, clinical management, outcomes, and costs of HIV disease in South Africa, Cote d'lvoire, and India. The current project has produced 16 publications, including a widely cited New England Journal of Medicine article, and another 9 submitted or draft manuscripts in its first 3 years. In this competing continuation, we request support to develop a 2nd generation CEPAC-International Model. This new model will reflect the most current understanding of HIV and AlDS epidemiology, treatment efficacy, impact on TB transmission and cost-effectiveness of care. The three specific aims of the current proposal are: 1) To refine the CEPAC-International Model's portrayal of critical patient- and population-level effects. This will include multiple entry cohorts staggered in time, person-to-person HIV transmission and TB transmission, long-term ART-related toxicities and co-morbidities, and to refine the approach to antiretroviral drug resistance. 2) To project clinical outcomes, cost, and cost-effectiveness of different patient-level treatment strategies for HIV care in developing countries;and 3) To identify optimal population-level HIV and AIDS treatment and prevention strategies in developing countries. The assembled research team has an extensive record of publishing and disseminating findings that inform priority setting in HIV care and practice guideline development, in the US and internationally. To augment the team's modeling capacity, skilled investigators with experience in HIV/TB co-infection, transmission dynamics as well as infectious disease modeling have been added to the team. By continuing the major progress already made by this multidisciplinary team, and accomplishing the specific aims described above, the proposed studies will address the most crucial HIV clinical policy and cost-effectiveness questions that will face providers and policy-makers in developing countries over the next several years. PUBLIC HEALTH RELEVANCE Despite recent progress globally to deliver HIV treatment and care to developing countries, major challenges remain in fully implementing these programs and understanding the clinical outcomes and cost-effectiveness of different strategies for HIV care worldwide. The CEPAC-International Model provides an inexpensive yet broadly applicable way of studying HIV interventions, projecting their outcomes, and highlighting important areas for future research. The flexibility of our program allows our team to investigate problems from several angles, providing insight into scenarios that may not be feasible to test in real-life settings through large-scale clinical trials.